Summary My overarching goal is to leverage the African killifish to test the functional significance of genes involved in rare pediatric diseases with progressive aging-like phenotypes, as a way to gain new insights into the mechanisms of tissue decline during normal human aging. The genetic architecture of human aging is not well understood and novel approaches are needed to identify new genes important for aging. Rare human diseases with aging-like phenotypes could provide new insights into the mechanisms of progressive decline in normal aging. Indeed, several rare pediatric diseases exhibit progressive tissue decline that are reminiscent of decline observed in normal aging. For example, Hutchinson-Gilford Progeria manifests with segmental aging- like phenotypes such as cardiovascular defects and muscle degeneration. Dyskeratosis congenita patients exhibit include premature anemia and gut dysfunctions. Remarkably, proteins that are involved in these diseases (Lamin A and telomerase, respectively) are also dysregulated during normal aging and have been functionally implicated in physiological aging. My specific hypothesis is that genes mutated in rare diseases of children with progressive aging-like phenotypes are also implicated in the mechanisms of tissue decline during normal aging. Through a collaboration with Drs. Stephen Montgomery and Mike Snyder, personalized genomics experts at Stanford, I obtained early access to lists of genes involved in new pediatric diseases with aging-like phenotypes. I propose to leverage the power of the short-lived African killifish, which has a naturally short lifespan and allows rapid genome-to-phenotype analyses. To understand the progressive changes in tissues with aging and aging-like diseases, I have started to generate transcriptomic profiling of brain, gut, heart, liver, and testis in young and old killifish. To test the idea that the genes involved in new rare diseases with aging-like phenotypes are implicated in tissue decline in these diseases and in normal aging, I will conduct the following experiments: 1. Test the causative role of human age-related genes and genetic variants in the killifish. 2. Evaluate gene expression changes during aging and progressive aging-like diseases across tissues in killifish and humans. My project provides an innovative framework to leverage personalized genomics data to identify genes involved in rare diseases with aging-like symptoms and in normal aging. By studying these extreme cases, I should not only gain insight into the mechanism of the diseases but also identify new genetic pathways that regulate normal aging. I am well prepared for this project, with my graduate training in human genetics and the mentoring of my sponsor and co-sponsor, Dr. Brunet and Dr. Wyss-Coray, to use the killifish as a model of aging. This project has excellent training potential to prepare me to run my own academic laboratory.